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Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease

Abstract

Genetic association studies have identified 215 risk loci for inflammatory bowel disease1,2,3,4,5,6,7,8, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

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Figure 1: Likely causal missense variants.
Figure 2: Colocalization of disease associations and stimulus response eQTLs in monocytes.
Figure 3: IBD-associated loci containing genes in immune pathways related to classes of approved therapeutics.

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Acknowledgements

We thank all individuals who contributed samples to the study. This work was co-funded by the Wellcome Trust (098051) and the Medical Research Council, UK (MR/J00314X/1). Case collections were supported by Crohn's and Colitis UK. K.M.d.L., L.M., C.A.L., Y.L., D.R., J.G.-A., N.J.P., C.A.A. and J.C.B. are supported by the Wellcome Trust (098051; 093885/Z/10/Z; 094491/Z/10/Z). K.M.d.L. is supported by a Woolf Fisher Trust scholarship. C.A.L. is a clinical lecturer funded by the NIHR. We thank A. Stanton for coordinating the patient recruitment at Guy's and St. Thomas'. We acknowledge support from the UK Department of Health via NIHR comprehensive Biomedical Research Centre awards to Guy's and St. Thomas' NHS Foundation Trust in partnership with King's College London and to Addenbrooke's Hospital, Cambridge, in partnership with the University of Cambridge. This research was also supported by the NIHR Newcastle Biomedical Research Centre. The UK Household Longitudinal Study is led by the Institute for Social and Economic Research at the University of Essex and funded by the Economic and Social Research Council. The survey was conducted by NatCen, and the genome-wide scan data were analyzed and deposited by the Wellcome Trust Sanger Institute. Information on how to access the data can be found on the Understanding Society website.

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Authors

Contributions

K.M.d.L., L.M., Y.L., L.J., D.L.R., C.A.A. and S.-G.J. performed statistical analysis. K.M.d.L., L.M., Y.L., L.J., J.C.L., J.G.-A., S.-G.J., C.A.L., N.A.K. and C.A.A. analyzed the data. G.H., E.R.N., C.E., C.M., A.S., D.C.W., M.T., A.H., C.G.M., M.P., W.G.M., C.W.L., H.U., C.H., N.J.P., T.A., J.C.M., J. Satsangi, J. Sanderson and P.H. contributed samples and/or materials. C.A.A., J.C.B., K.M.d.L., L.M., J.C.L., C.G.M., M.P., C.A.L., N.A.K., Y.L. and P.H. wrote the manuscript. J.C.B., C.A.A., J.C.M., M.P., C.W.L., T.A. and N.J.P. conceived and designed experiments.

Corresponding authors

Correspondence to Carl A Anderson or Jeffrey C Barrett.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Manhattan plot of meta-analysis summary statistics for Crohn’s disease.

Loci previously associated with IBD are shown in orange, those previously associated with Crohn’s disease are shown in red and those previously associated with ulcerative colitis are shown in dark blue.

Supplementary Figure 2 Manhattan plot of meta-analysis summary statistics for ulcerative colitis.

Loci previously associated with IBD are shown in orange, those previously associated with Crohn’s disease are shown in red and those previously associated with ulcerative colitis are shown in dark blue.

Supplementary Figure 3 Manhattan plot of meta-analysis summary statistics for inflammatory bowel disease.

Loci previously associated with IBD are shown in orange, those previously associated with Crohn’s disease are shown in red and those previously associated with ulcerative colitis are shown in dark blue.

Supplementary Figure 4 Cluster plots for variant rs34687326.

Cluster plots were created for directly genotyped variants in loci that were precisely fine-mapped using individuals in the new UKIBDGC GWAS.

Supplementary Figure 5 Cluster plots for variant rs1143687.

Cluster plots were created for directly genotyped variants in loci that were precisely fine-mapped using individuals in the new UKIBDGC GWAS.

Supplementary Figure 6 Cluster plots for variant rs4821544.

Cluster plots were created for directly genotyped variants in loci that were precisely fine-mapped using individuals in the new UKIBDGC GWAS.

Supplementary Figure 7 Effect size of variant rs4821544 when stratified by disease location.

The effect of this variant that was fine-mapped well, which is intronic in NCF4, is consistently stronger in small bowel than in large bowel disease.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 1206 kb)

Supplementary Table 1

GWAS, sequencing and summary statistic data sets included in this study. (XLSX 32 kb)

Supplementary Table 2

Meta-analysis association statistics at all 241 known and novel loci. (XLSX 74 kb)

Supplementary Table 3

Fine-mapping summary statistics for 65 loci where fine-mapping was attempted. (XLSX 116 kb)

Supplementary Table 4

Enrichment of known IBD loci for genes associated with Mendelian disorders of inflammation and immunity. (XLSX 54 kb)

Supplementary Table 5

Colocalization between meta-analysis association statistics and monocyte stimulus response eQTLs. (XLSX 9 kb)

Supplementary Table 6

IBD-associated loci containing genes in immune pathways related to classes of approved therapeutics. (XLSX 9 kb)

Supplementary Table 7

Overlap of 25 novel IBD-associated loci with known eQTL signals. (XLSX 297 kb)

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de Lange, K., Moutsianas, L., Lee, J. et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nat Genet 49, 256–261 (2017). https://doi.org/10.1038/ng.3760

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